Substituted porphyrin and azaporphyrin derivatives and their use in photodynamic therapy, radioimaging and MRI diagnosis

Abstract

Substituted porphyrin and azaporphyrin deviations with various substitutents in the 12- and 17-positions of the porphyrin skeleton as pharmaceutical agents for use in photodynamic therapy, MRI diagnosis, and radiodiagnostics.

1. A compound of formula II: 
                 
 wherein R 1 -R 11  can be the same or different and are selected from: H, halide, substituted or unsubstituted alkyl, heteroalkyl, haloalkyl, heterohaloalkyl, cyclic alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, ether, polyether, alkoxy group, aryloxy group, haloalkoxy group, amino group, alkylcarbonyloxy group, alkoxycarbonyl group, aryloxycarbonyl group, azo group, arylcarbonyloxy group, alkoxycarbonyloxy group, aryloxycarbonyloxy group, sulfinyl group, sulfonyl group, silil group, carbamoyl group, heterocyclic group, nitro group, nitroso group, formyloxy group, isocyano group, cyanate group, isocyanate group, thiocyanate group, isothiocyanate group, N(alkyl) 2 , N(aryl) 2 , CH═CH(aryl), CH═CHCH 2 N(CH 3 ) 2 , or a functional group of molecular weight of less than about 100,000 daltons; CH═CHCH 2 N + (CH 3 ) 3 A, CH═N(alkyl) 2 A, or N(alkyl) 3   + A, where A is a charge balancing ion; CN, OH, CHO, COCH 3 , CO(alkyl), CO 2 H, CO 2 Na, CO 2 K, CH(CH 3 )OH, CH(CH 3 )O-alkyl, CH(CH 3 )O-alkoxy, and CH(CH 3 )O-aryl;  
 (CH 2 ) n O-alkoxy, or (CH 2 ) n O-alkyl, where n is an integer from 0 to 8;  
 C(X) 2 C(X) 3 , where X is a halogen;  
 CO 2 R 12 , where R 12  is selected from a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons;  
 (CH 2 ) n OH, or (CH 2 ) n OR 13 , where R 13  is selected from alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a protecting group, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;  
 (CH 2 ) n CO 2 R 14 , (CHX) n CO 2 R 14 , or (CX 2 ) n CO 2 R 14 , where X is a halogen and R 14  is selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalky;, aryl, heteroaryl, heterocycle, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 1 and 4;  
 CONH(R 15 ), CONHNH(R 15 ), CO(R 15 ), CON(R 15 ) 2 , CON(R 15 )(R 16 ), (CH 2 ) n CONH(R 15 ), (CH 2 ) n CONHNH(R 15 ), (CH 2 ) n CON(R 15 ) 2 , (CH 2 ) n COR 15 , (CH 2 ) n CON(R 15 )(R 16 ), (CX 2 ) n CONH(R 15 ), (CX 2 ) n CON(R 15 ) 2 , (CX 2 ) n CON(R 15 )(R 16 ) (CX 2 ) n COR 15 , (CH 2 ) n CONHNH(R 15 ), (CX 2 ) n CONHNH(R 15 ), (CHX) n CONH(R 15 ), (CHX) n CONHNH(R 15 ), (CHX) n CON(R 15 ) 2 , (CHX) n CON(R 15 )(R 16 ) where X is a halogen and R 15  and R 16  can be the same or different and are selected from H, NH 2 , straight or branched chain C1-C20 alkyl, haloalkyl, haloheteroalkyl, heteroalkyl, aryl, heteroaryl, heterocycle, a mono-, di-, or Polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, an amino acid, an amino acid salt, an amino acid ester, an amino acid amide, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;  
 S(R 17 ), (CH 2 ) n S(R 17 ), (CH 2 ) n NH(R 17 ), (CH 2 ) n NH(R 17 ), (CH 2 ) n R 17 , (CH 2 ) n N(R 17 )(R 18 ), or (CH 2 ) n N(R 17 )(R 18 )(R 19 ) + A where R 17 , R 18  and R 19  can be the same or different and are selected from H, NH 2 , straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, heterocycle, amino acids, an amino acid ester, an amino acid amide provided —NH(R 17 ) is part of the amino acid, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, a functional group of less than about 100,000 daltons, or where R 17 , R 18  and R 19  together possess the atoms necessary to constitute an aromatic ring system, n is an integer between 0 and 4, and A is a physiologically acceptable counter ion;  
 (CH 2 ) n OPO 2 OR 20 , (CH 2 ) n PO(OR 20 ) 2 , (CH 2 ) n PO 2 R 20 , or (CH 2 ) n POR 20  where R 20  is selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl or heteroaryl, heterocycle, amino acids and salts, esters, or amides thereof, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;  
 (CH 2 ) n NHCOR 21 , or (CH 2 ) n NHNHCOR 21 , where R 21  is selected from a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, heterocycle, amino acids and salts, esters, or amides thereof, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;  
 SO 3 R 22 , SO 2 NHR 22 , SO 2 N(R 22 ) 2 , SO 2 NHNHR 22  or SO 2 R 22 , where R 22  is select H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl or heteroaryl, heterocycle, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, and NHR 22  can be an amino acid residue, an amino acid salt, an amino acid ester residue, an amino acid amide residue, or a functional group of less than about 100,000 daltons;  
 Aryl or substituted aryl, which may bear one or more substituents with a molecular weight of less than or equal to about 100,000 daltons;  
 R 1 —R 2 , R 3 —R 4 , R 6 —R 7 , R 9 —R 10 , R 4 —R 5 , R 5 —R 6 , R 7 —R 8 , R 8 —R 9 , R 10 —R 11 , or R 11 —R 1 , may also possess the atoms necessary to form ring systems, which themselves may possess heteroatoms that may bear one or more functional groups of molecular weight equal to or less than about 100,000 daltons;  
 with the proviso that at least one of the R 1 -R 11  groups is linked via an organic group that has as part or all of its structure a group Q, which is an amine, an ester, an ether or an amide link, to a complexing agent of general formula IIa, IIb, IIc, IId, IIe: 
                 
 
 
       wherein R 24  is selected from a hydrogen, a straight or branched chain C 1 -C 7  alkyl group, a phenyl or benzyl group; L 1 , L 2 , L 3 , L 4 , independently of one another, are selected from a hydrogen atom or a metal ion equivalent of an element of the atomic numbers 20-32, 37-39, 42-51, or 57-83, which may be radioactive, provided that at least two of L 1 , L 2 , L 3  and L 4  are metal ion equivalents, that other anions are present to compensate for optionally present charges on the porphyrin, and free carboxyhic acid groups that are not required for complexing are optionally present as salts with physiologically compatible inorganic cations, or organic cations, or as esters or amides; and wherein
 M is 2H or a diamagnetic or paramagnetic photoactive metal ion selected from Ga 3+ , Pt 2+ , Pd 2+ , Sn 4+ , In 3+ , Ge 4+ , Si 4+ , Al 3+ , Zn 2+ , and Mg 2+ .  
 
     
     
       2. A method of using the compound of  claim 1  comprising administering the compound to a patient and, after a period of time, imaging targeted tissue of the patient through MRI or radio-diagnostic imaging. 
     
     
       3. A method of using the compound of  claim 1  comprising administering the compound to a patient and, after a period of time, irradiating targeted tissue of the patient with an energy source that excites the compound thereby producing a desired therapeutic response in the target tissue. 
     
     
       4. A method of using the compound of  claim 1  comprising administering the compound to a patient and, after a period of time, imaging targeted tissue of the patient through MRI or radio-diagnostic imaging then, after a second period of time, irradiating the targeted tissue with an energy source that excites the compound thereby producing a desired therapeutic response in the target tissue. 
     
     
       5. A method for the detection or treatment of tissue comprising administering to a patient a therapeutic amount of the compound of  claim 1  locally, systemically, intramuscularly or interperitoneally and irradiating said compound with energy at a wavelength able to excite the molecule, such that a desired therapeutic effect is observed, whereby said tissue belongs to the hematological system, lymphatic reticuloendothelial system, nervous system, endocrine and exocrine system, skeletomuscular system, skin, pulmonary system, gastrointestinal, reproductive system, immune system, cardiovascular system, urinary system, auditory or olfactory system. 
     
     
       6. The method of  claim 2 , wherein said method is for diagnosing disorders in a vessel wall, tissue adjoining the vessel wall, or material attached to the vessel wall of a coronary, carotid or peripheral vasculature. 
     
     
       7. The method of  claim 6  wherein said vessel is an artery or a vein. 
     
     
       8. The method of  claim 2  wherein the tissue is atherosclerosis, restenosis or graft disease. 
     
     
       9. The method of  claim 3  wherein the tissue is atherosclerosis, restenosis or graft disease. 
     
     
       10. The method of  claim 4  wherein the tissue is atherosclerosis, restenosis or graft disease. 
     
     
       11. The method of  claim 5  wherein the tissue is atherosclerosis, restenosis or graft disease. 
     
     
       12. The method of  claim 4  wherein the therapy is selected from ablation, reduction and stabilization of vessel wall plaque. 
     
     
       13. The method of  claim 4  wherein said energy source is selected from light, ultrasound, magnetic force, and electromagnetic radiation in the UV/visible electromagnetic spectrum or near infrared. 
     
     
       14. The method of  claim 4  wherein said administration of the compound is prior to, concomitant with, or subsequent to adjunctive interventions, diagnostics or therapies. 
     
     
       15. The method of  claim 4  wherein said administration is a single bolus or plurality of doses administered to the patient. 
     
     
       16. A compound of formula IIA: 
                 
 wherein R 1 -R 6  can be the same or different and are selected from: H, halide, substituted or unsubstituted alkyl, heteroalkyl, haloalkyl, heterohaloalkyl, cyclic alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, ether, polyether, alkoxy group, aryloxy group, haloalkoxy group, amino group, alkylcarbonyloxy group, alkoxycarbonyl group, aryloxycarbonyl group, azo group, arylcarbonyloxy group, alkoxycarbonyloxy group, aryloxycarbonyloxy group, sulfinyl group, sulfonyl group, silil group, carbamoyl group, heterocyclic group, nitro group, nitroso group, formyloxy group, isocyano group, cyanate group, isocyanate group, thiocyanate group, isothiocyanate group, N(alkyl) 2 , N(aryl) 2 , CH═CH(aryl), CH═CHCH 2 N(CH 3 ) 2 , or a functional group of molecular weight of less than about 100,000 daltons; CH═CHCH 2 N + (CH 3 ) 3 A, CH═N(alkyl) 2 A, or N(alkyl) 3   + A, where A is a charge balancing ion; CN, OH, CHO, COCH 3 , CO(alkyl), CO 2 H, CO 2 Na, CO 2 K, CH(CH 3 )OH, CH(CH 3 )O-alkyl, CH(CH 3 )O-alkoxy, or CH(CH 3 )O-aryl;  
 (CH 2 ) n O-alkoxy, or (CH 2 ) n O-aIkyl, where n is an integer from 0 to 8;  
 C(X) 2 C(X) 3 , where X is a halogen;  
 CO 2 R 7 , where R 7  is selected from a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, heterocycle, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons;  
 (CH 2 ) n OH, or (CH 2 ) n OR 8 , where R 8  is selected from alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, heterocycle, a protecting group, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;  
 (CH 2 ) n CO 2 R 9 , (CHX) n CO 2 R 9 , or (CX 2 ) n CO 2 R 9 , where X is a halogen and R 9  is selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 1 and 4;  
 CONH(R 10 ), CONHNH(R 10 ), CO(R 10 ), CON(R 10 ) 2 , CON(R 10 )(R 11 ), (CH 2 ) n CONH(R 10 ), (CH 2 ) n CONHNH(R 10 ), (CH 2 ) n CON(R 10 ) 2 , (CH 2 ) n COR 10 , (CH 2 ) n CON(R 10 )(R 11 ), (CX 2 ) n CONH(R 10 ), (CX 2 ) n CON(R 10 ) 2 , (CX 2 ) n CON(R 10 )(R 11 ), (CX 2 ) n COR 10 , (CH 2 ) n CONHNH(R 10 ), (CX 2 ) n CONHNH(R 10 ), (CHX) n CONH(R 10 ), (CHX) n CONHNH(R 10 ), (CHX) n CON(R 10 ) 2 , or (CHX) n CON(R 10 )( R 11 ), where X is a halogen and R 10  and R 11  can be the same or different and are selected from H, NH 2 , straight or branched chain C1-C20 alkyl, haloalkyl, haloheteroalkyl, heteroalkyl, aryl, heteroaryl, heterocycle, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, an amino acid, an amino acid salt, an amino acid ester, an amino acid amide, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;  
 S(R 12 ), (CH 2 ) n S(R 12 ), (CH 2 ) n NH(R 12 ), (CH 2 ) n NHNH(R 12 ), (CH 2 ) n N(R 12 ) 2 , (CH 2 ) n N(R 12 )(R 13 ), or (CH 2 ) n N(R 12 )(R 13 )(R 14 ) + A, where R 12 , R 13  and R 14  can be the same or different and are selected from H, NH 2 , straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, heterocycle, amino acids, an amino acid ester, or an amino acid amide provided —NH(R 13 ) is part of the amino acid, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, a functional group of less than about 100,000 daltons, or where R 12 , R 13  and R 14  together possess the atoms necessary to constitute an aromatic ring system, n is an integer between 0 and 4, and A is a physiologically acceptable counter ion;  
 (CH 2 ) n OPO 2 OR 15 , (CH 2 ) n PO(OR 15 ) 2 , (CH 2 ) n PO 2 R 15 , or (CH 2 ) n POR 15  where R 15  is selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl or heteroaryl, heterocycle, amino acids and salts, esters, or amides thereof, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;  
 (CH 2 ) n NHCOR 16 , or (CH 2 ) n NHNHCOR 16 , where R 16  is selected from a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, heterocycle, amino acids and salts, esters, or amides thereof, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;  
 SO 3 R 17 , SO 2 NHR 17 , SO 2 N(R 17 ) 2 , SO 2 NHNHR 17  or SO 2 R 17 , where R 17  is select H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, heterocycle, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, a functional group of less than about 100,000 daltons, and NHR 17  can be an amino acid residue, an amino acid salt, an amino acid ester residue, an amino acid amide residue;  
 Aryl or substituted aryl, which may bear one or more substituents with a molecular weight of less than or equal to about 100,000 daltons; and  
 R 1 —R 2 , and R 3 —R 4  may also possess the atoms necessary to form ring systems, which themselves may possess heteroatoms that may bear one or more functional groups of molecular weight equal to or less than about 100,000 daltons;  
 with the proviso that at least one of the R 1 -R 4  groups is linked via an organic group that has as part or all of its structure a group Q, which is an amine, an ester, an ether or an amide link, to a complexing agent of general formula IIa, IIb, IIc, IId, IIe: 
                 
 
 wherein R 24  is selected from a hydrogen, a straight or branched chain C 1 -C 7  alkyl group, a phenyl or benzyl group; L 1 , L 2 , L 3 , L 4 , independently of one another, are selected from a hydrogen atom or a metal ion equivalent of an element of the atomic numbers 20-32, 37-39, 42-51, or 57-83, which may be radioactive, provided that at least two of L 1 , L 2 , L 3  and L 4  are metal ion equivalents, that other anions are present to compensate for optionally present charges on the porphyrin, and free carboxylic acid groups that are not required for complexing are optionally present as salts with physiologically compatible inorganic cations, or organic cations, or as esters or amides; and wherein  
 M is 2H or a diamagnetic or paramagnetic photoactive metal ion selected from Ga 3+ , Pt 2+ , Pd 2+ , Sn 4+ , In 3+ , Ge 4+ , Si 4+ , Al 3+ , Zn 2+ , and Mg 2+ .  
 
     
     
       17. A method of using the compound of  claim 16  comprising administering the compound to a patient and, after a period of time, imaging targeted tissue of the patient through MRI or radio-diagnostic imaging. 
     
     
       18. A method of using the compound of  claim 16  comprising administering the compound to a patient and, after a period of time, irradiating targeted tissue of the patient with an energy source that excites the compound thereby producing a desired therapeutic response in the target tissue. 
     
     
       19. A method of using the compound of  claim 16  comprising administering the compound to a patient and, after a period of time, imaging targeted tissue of the patient through MRI or radio-diagnostic imaging then, after a second period of time, irradiating the targeted tissue with an energy source that excites the compound thereby producing a desired therapeutic response in the target tissue. 
     
     
       20. A method for the detection or treatment of tissue comprising administering to a patient a therapeutic amount of the compound of  claim 16  locally, systemically, intramuscularly or interperitoneally and irradiating said compound with energy at a wavelength able to excite the molecule, such that a desired therapeutic effect is observed, whereby said tissue belongs to the hematological system, lymphatic reticuloendothelial system, nervous system, endocrine and exocrine system, skeletomuscular system, skin, pulmonary system, gastrointestinal, reproductive system, immune system, cardiovascular system, urinary system, auditory or olfactory system. 
     
     
       21. The method of  claim 17 , wherein said method is for diagnosing disorders in a vessel wall, tissue adjoining the vessel wall, or material attached to the vessel wall of a coronary, carotid or peripheral vasculature. 
     
     
       22. The method of  claim 21  wherein said vessel is an artery or a vein. 
     
     
       23. The method of  claim 17  wherein the tissue is atherosclerosis, restenosis or graft disease. 
     
     
       24. The method of  claim 18  wherein the tissue is atherosclerosis, restenosis or graft disease. 
     
     
       25. The method of  claim 19  wherein the tissue is atherosclerosis, restenosis or graft disease. 
     
     
       26. The method of  claim 20  wherein the tissue is atherosclerosis, restenosis or graft disease. 
     
     
       27. The method of  claim 19  wherein the therapy is selected from ablation, reduction and stabilization of vessel wall plaque. 
     
     
       28. The method of  claim 19  wherein said energy source is selected from light, ultrasound, magnetic force, and electromagnetic radiation in the UV/visible electromagnetic spectrum or near infrared. 
     
     
       29. The method of  claim 19  wherein said administration of the compound is prior to, concomitant with, or subsequent to adjunctive interventions, diagnostics or therapies. 
     
     
       30. The method of  claim 19  wherein said administration is a single bolus or plurality of doses administered to the patient.